Genetic Variant KCNMA1:c.*2025_*2026dupTA (chr10-76885239-T-TTA) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001161352.2(KCNMA1):c.*2025_*2026dupTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 480,628 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 30)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.715

Publications

0 publications found

Variant links:

Genes affected

KCNMA1 (HGNC:6284): (potassium calcium-activated channel subfamily M alpha 1) This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]

KCNMA1 Gene-Disease associations (from GenCC):

generalized epilepsy-paroxysmal dyskinesia syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
Liang-Wang syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
cerebellar atrophy, developmental delay, and seizures
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

KCNMA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00103 (152/147468) while in subpopulation EAS AF = 0.0176 (90/5122). AF 95% confidence interval is 0.0146. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.2025_2026dupTA		3_prime_UTR_variant	Exon 28 of 28	ENST00000286628.14	NP_001154824.1	Q12791-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 link	c.2025_2026dupTA		3_prime_UTR_variant	Exon 28 of 28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

152

AN:

147468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000679

Gnomad ASJ

AF:

0.00174

Gnomad EAS

AF:

0.0175

Gnomad SAS

AF:

0.000419

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000895

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000147

AC:

AN:

333160

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

159154

show subpopulations

African (AFR)

AF:

0.000821

AC:

AN:

6090

American (AMR)

AF:

0.00

AC:

AN:

1008

Ashkenazi Jewish (ASJ)

AF:

0.00244

AC:

AN:

2464

East Asian (EAS)

AF:

0.0108

AC:

AN:

2406

South Asian (SAS)

AF:

0.00

AC:

AN:

6332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

714

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

302294

Other (OTH)

AF:

0.000267

AC:

AN:

11250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00103

AC:

152

AN:

147468

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

71860

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

40632

American (AMR)

AF:

0.0000679

AC:

AN:

14738

Ashkenazi Jewish (ASJ)

AF:

0.00174

AC:

AN:

3444

East Asian (EAS)

AF:

0.0176

AC:

AN:

5122

South Asian (SAS)

AF:

0.000421

AC:

AN:

4746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000895

AC:

AN:

67062

Other (OTH)

AF:

0.00

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.71

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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10-76885239-T-TTA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over